piperidines and Hypertension--Renovascular

Renovascular hypertension (RVH) is a common cause of both cardiovascular and renal morbidity and mortality. In renal artery stenosis (RAS), atrophy in the stenotic kidney is associated with an influx of macrophages and other mononuclear cells. We tested the hypothesis that chemokine receptor 2 (CCR2) inhibition would reduce chronic renal injury by reducing macrophage influx in the stenotic kidney of mice with RAS. We employed a well-established murine model of RVH to define the relationship between macrophage infiltration and development of renal atrophy in the stenotic kidney. To determine the role of chemokine ligand 2 (CCL2)/CCR2 signaling in the development of renal atrophy, mice were treated with the CCR2 inhibitor RS-102895 at the time of RAS surgery and followed for 4 wk. Renal tubular epithelial cells expressed CCL2 by 3 days following surgery, a time at which no significant light microscopic alterations, including interstitial inflammation, were identified. Macrophage influx increased with time following surgery. At 4 wk, the development of severe renal atrophy was accompanied by an influx of inducible nitric oxide synthase (iNOS)+ and CD206+ macrophages that coexpressed F4/80, with a modest increase in macrophages coexpressing arginase 1 and F4/80. The CCR2 inhibitor RS-102895 attenuated renal atrophy and significantly reduced the number of dual-stained F4/80+ iNOS+ and F4/80+ CD206+ but not F4/80+ arginase 1+ macrophages. CCR2 inhibition reduces iNOS+ and CD206+ macrophage accumulation that coexpress F4/80 and renal atrophy in experimental renal artery stenosis. CCR2 blockade may provide a novel therapeutic approach to humans with RVH.

Topics: Animals; Antigens, Differentiation; Arginase; Atrophy; Benzoxazines; Chemokine CCL2; Cytoprotection; Disease Models, Animal; Hypertension, Renovascular; Kidney; Lectins, C-Type; Macrophages; Male; Mannose Receptor; Mannose-Binding Lectins; Mice, Inbred C57BL; Mice, Transgenic; Molecular Targeted Therapy; Nephritis, Interstitial; Nitric Oxide Synthase Type II; Piperidines; Protective Agents; Receptors, CCR2; Receptors, Cell Surface; Renal Artery Obstruction; Signal Transduction; Time Factors

Dysregulation of the autonomic nervous system is frequent in subjects with cardiovascular disease. The contribution of different forms of renovascular hypertension and the mechanisms contributing to autonomic dysfunction in hypertension are incompletely understood. Here, murine models of renovascular hypertension with preserved (2-kidneys-1 clip, 2K1C) and reduced (1-kidney-1 clip, 1K1C) kidney mass were studied with regard to autonomic nervous system regulation (sympathetic tone: power-spectral analysis of systolic blood pressure; parasympathetic tone: power-spectral analysis of heart rate) and baroreflex sensitivity of heart rate by spontaneous, concomitant changes of systolic blood pressure and pulse interval. Involvement of the renin-angiotensin system and the rho-kinase pathway were determined by application of inhibitors.. C57BL6N mice (6 to 11) with reduced kidney mass (1K1C) or with preserved kidney mass (2K1C) developed a similar degree of hypertension. In comparison to control mice, both models presented with a significantly increased sympathetic tone and lower baroreflex sensitivity of heart rate. However, only 2K1C animals had a lower parasympathetic tone, whereas urinary norepinephrine excretion was reduced in the 1K1C model. Rho kinase inhibition given to a subset of 1K1C and 2K1C animals improved baroreflex sensitivity of heart rate selectively in the 1K1C model. Rho kinase inhibition had no additional effects on autonomic nervous system in either model of renovascular hypertension and did not change the blood pressure. Blockade of AT1 receptors (in 2K1C animals) normalized the sympathetic tone, decreased resting heart rate, improved baroreflex sensitivity of heart rate and parasympathetic tone.. Regardless of residual renal mass, blood pressure and sympathetic tone are increased, whereas baroreflex sensitivity is depressed in murine models of renovascular hypertension. Reduced norepinephrine excretion and/or degradation might contribute to sympathoactivation in renovascular hypertension with reduced renal mass (1K1C). Overall, the study helps to direct research to optimize medical therapy of hypertension.

Topics: Animals; Baroreflex; Blood Pressure; Disease Models, Animal; Heart Rate; Hypertension, Renovascular; Isoquinolines; Kidney; Mice; Mice, Inbred C57BL; Parasympathetic Nervous System; Piperidines; rho-Associated Kinases; Sympathetic Nervous System

The antihypertensive effects of intravenous injection of ketanserin, a 5-HT2 receptor antagonist, were assessed in conscious rabbits. In intact rabbits, ketanserin lowered blood pressure in a dose-dependent manner. The antihypertensive effects of ketanserin were also observed in rabbits with two-kidney, one clip (2K1C) hypertension and with one-kidney, one clip (1K1C) hypertension. The effect was more marked in the 1K1C rabbits with low plasma renin activity (PRA) and high plasma norepinephrine (PNE) than in 2K1C rabbits with high PRA and normal PNE. The heart rate was not changed. Ketanserin suppressed the pressor response to exogenous norepinephrine (0.6 micrograms/Kg) 15, 30 and 45 min after the injection of ketanserin (1 mg/Kg). It also suppressed the pressor response to phenylephrine (3 micrograms/Kg) 15 min after the injection, but it did not suppress the pressor response to angiotensin II (0.15 micrograms/Kg). In order to investigate baroreceptor function, balloons were placed around the abdominal aorta and the inferior vena cava and inflated alternately. Thus, the mean arterial pressure vs heart period-logistic curve was obtained under steady-state conditions. There were no changes after the drug administration in the range of heart period and the gain (the slope at midpoint of the curve). These results suggest that the inhibition of pressor response of norepinephrine has effects in addition to a direct vasodilatory action and that an alteration of baroreceptor function is not involved in the antihypertensive effects of ketanserin.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Heart Rate; Hypertension, Renovascular; Injections, Intravenous; Ketanserin; Male; Norepinephrine; Piperidines; Rabbits; Renin; Serotonin Antagonists